Alkaloid inspired spirocyclic oxindoles from 1,3-dipolar cycloaddition of pyridinium ylides

Abstract

Cycloaddition reactions between pyridinium ylides and 3-alkenyl oxindoles that proceed in high yield and with very good regio- and diastereoselectivity are reported. The resulting cycloadducts have the same stereochemistry of biologically active oxindole alkaloids, such as strychnofoline.

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Introduction

Natural products and their signature fragments are an enduring resource for identifying biological modulators.¹ A number of biologically active alkaloids, such as strychnofoline and isorhynchophylline (Fig. 1), feature spiroindolizidine oxindoles.^2,3 This fragment is considered ‘privileged’ for potential therapeutic investigation and there is much interest in developing expedient synthesis of such structures.⁴

Fig. 1 Example spirooxindole alkaloids.

Target spiroindolizidineoxindole structures may be efficiently accessed by 1,3-dipolar cycloaddition of 3-alkylideneindoline-2-ones.⁵ Serov et al. described reactions between N-phenylacylquinolinium ylides with 3-alkylidene oxindoles,⁶ while extended studies of this type of reaction have recently been reported.⁷ The latter cycloadducts have a relatively high molecular weight due to additional aromatic rings and it is not easy to envisage strategies for their transformation into natural products or drug-like scaffolds.

There are no literature descriptions of corresponding 1,3-dipolar cycloadditions of pyridinium ylides to 3-alkylidene oxindoles, yet such cycloadducts would be attractive for access to spirooxindole alkaloids and possible therapeutics. Cycloaddition reactions of pyridinium ylides have previously been reported but in situ oxidation is commonly used, leading to valuable unsaturated indolizines.⁸ Of course, such oxidations destroy the rich stereochemical information accumulated during the cycloaddition. Early investigation of general pyridinium ylide cycloadditions noted limited stability of the tetrahydroindolizine cycloadducts and this may have discouraged further investigation of these products.⁹ The 1,2-dihydropyridine motif embedded within tetrahydroindolizine cycloadducts is generally regarded as unstable with few exceptions,¹⁰ although there have been exciting developments in unlocking their synthetic potential.¹¹

This report demonstrates that cycloaddition reactions between pyridinium ylides 2 (Table 1) and 3-alkylidene oxindoles 1 proceed with good selectivity to produce generally isolable spirotetrahydroindolizineoxindole cycloadducts 3 in good yield.

Table 1 Optimisation of conditions

Solvent	Base	Time (h)	Yield^a (%)
a Yield after chromatography.
Toluene	Et3N	3	65
EtOAc	Et3N	4	64
CH2Cl2	Et3N	2	88
DMF	Et3N	1	61
EtOH	Et3N	4	40
CH2Cl2	DBU	3	73
CH2Cl2	^tBuOK	3	71
THF	NaH	2	82

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Results and discussion

Starting materials for this route are readily accessible by olefination of isatin to give 3-alkylidene-2-oxindoles;¹²† pyridinium salts were obtained by alkylation.¹³† Pyridinium salts featuring N-methylene groups attached to an electron withdrawing group can be readily deprotonated using mild base to give the ylide.^14,15

Initially, we set out to briefly investigate the role of solvent and base on yield. An excess of pyridinium salt 2a relative to dipolarophiles 1a was used to suppress further cycloaddition onto the initial tetrahydroindolizine product.⁹

Generally, high yields of cycloadduct were obtained using a variety of solvents and base at room temperature, although suspending the reagents in dichloromethane, then initiating the reaction by addition of triethylamine is convenient (Table 1). The cycloadduct 3a is stable to chromatography and could be stored under argon in the freezer for no more than a week.

Cycloaddition between the ylide derived from 3-bromopyridinium salt 2a and oxindole 1a appears to be highly regio- and diastereoselective, giving a single product 3a (Table 1). ¹H-NMR spectroscopy of the cycloadduct revealed an apparent triplet for the 5′ proton (J = 7.0 Hz) indicative of reaction at the C-2 position of the pyridinium salt. Initial NOESY analysis revealed enhancements between protons corresponding to 1′ ring junction and 2′ position adjacent to the spirocentre, but not between the 1′ and 3′ positions adjacent to nitrogen.

Ultimately, single crystal X-ray diffraction of this material gave unequivocal evidence of the diastereoselectivity of the reaction (Fig. 2).‡ The relative stereochemistry of the spirocentre (position 8a′) and the 1′ position is diagnostic of exo or endo selectivity; co-location of the oxindole carbonyl and 1′ proton on the same face of the cycloadduct is suggestive of an attractive interaction between the electron rich oxindole aromatic ring and the electron deficient pyridinium in the transition state. The trans arrangement of the 1′ and 3′ protons is also confirmed, indicating that the ylide is S-shaped in the transition state (Scheme 1). This relative stereochemistry is the same as that required for alkaloids related to strychnofoline and isorhynchophylline.

Fig. 2 Crystal structure of cycloadduct 3a (CCDC 927103). Ellipsoids are drawn at the 50% probability level.

Scheme 1 Proposed origin of observed diastereoselectivity.

We next carried out investigation into the generality of the reaction using various 3-alkylideneoxindoles 1b–f (Table 2).¹¹† Cycloaddition with the ylide derived from 3-bromopyridinium salt 2a generally proceeded to give good yields (80–90%) of cycloadducts 3b–f as single diastereoisomers with relative stereochemistry similar to cycloadduct 3a as judged by ¹H NMR spectroscopy. 3-Methylene oxindole 1f is a stable solid that readily undergoes cycloaddition reactions in good yield (entry 5). Unfortunately, N-substituted 3-methylene oxindoles are highly reactive and generally met with polymerisation before cycloaddition could be attempted.¹⁶ On the other hand, N-propargyl and N-acetyl substituted oxindoles (entries 3 and 4, 1d and 1e respectively) bearing an ethyl ester gave good yields of cycloadducts (3d and 3e respectively).

Table 2 Cycloaddition with varied oxindoles

Entry	Oxindole	Cycloadduct	Yield^a (%)
a Yield after chromatography.
1			93
2			91
3			82
4			83
5			81

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A selection of pyridinium salts (2g–l) were also evaluated (Table 3). Cycloadducts arising from reaction with unsubstituted pyridinium salt (2l) could be detected by mass spectrometry of the reaction mixture but were not stable to purification by chromatography, however the saturated indolizidine 3l could be obtained by in situ reduction using RANEY® nickel in good yield.

Table 3 Cycloaddition with various pyridinium salts

Entry	Pyridinium salt	Cycloadduct	Yield^a (%) [ratio]
a Yield after chromatography.b Inseparable mixture of two diastereoisomers, ratio in parenthesis from relative integration of ^1H NMR spectrum.c Crude cycloadduct subject to H2/RANEY® nickel (∼10 mol%) in EtOAc.
1			77 [2 : 1]^b
2			95 [7 : 3]^b
3			81 [1 : 1]^b
4			76
5			87
6			63^c

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Pyridinium salts featuring methyl, or phenyl substituents at the 3- or 4-pyridinium position (not shown) did not give observable products in their respective cycloaddition reactions using these condition, which we presume to be due to their instability.

Pleasingly, less acidic pyridinium salts featuring either nitrile (2m) or phenyl (2n) ylide stabilising groups could be deprotonated with sodium hydride, leading to good yields of the corresponding cycloadducts 3m and 3n respectively as single diastereoisomers (Scheme 2).

Scheme 2 Reagents and conditions: a, NaH (2 equiv.), THF, rt.

Pyridinium salts featuring resonance stabilising groups (2g–i) in the 3-position gave good overall yields of spiroindolizidine oxindoles arising from reaction at the C-6 position of the pyridinium ring, i.e. opposite to the electron withdrawing substituent. These products (3g–i) were obtained as a mixture of two diastereoisomers in varying ratios.

Crystals were obtained from the 3-cyanopyridine derived cycloadduct 3g that X-ray diffraction revealed to feature the 1′ proton on the opposite face to the oxindole carbonyl (Fig. 3).‡ This product was later confirmed as the minor diastereoisomer 3g′ by ¹H NMR spectroscopy.

Fig. 3 Crystal structure of the minor diastereoisomer of cycloadduct 3g′ (CCDC 927102). Ellipsoids are drawn at the 50% probability level.

There are two possible explanations for these observed results. One is that pyridinium resonance stabilising groups influence the orientation of the transition state. Alternatively, interconversion of cycloadducts via ring opening to restore the pyridinium ring, then rotation about the former 2′–8′a bond and rejoining of the enolate with the pyridinium may proceed.¹⁷ An analogous reversible Mannich reaction mechanism is well known to occur in either acidic or basic media, leading to interchange between related spirocyclic oxindole alkaloid diastereoisomers, such as isorhynchophylline and rhynchophylline.¹⁸ Diastereoisomer 3g′ remained unchanged when exposed to the same cycloaddition conditions for 14 hours, however.¹⁹

A recent paper described reactions of very closely related pyridinium ylides and 3-alkylideneoxindoles in ethanol with 20 mol% triethylamine at 50 °C, but alkene products arising from elimination of pyridine were the exclusive reported products.²⁰ A similar reaction product was obtained when the cycloaddition reaction between pyridinium ylide 2l with 3-alkylideneoxindole 1a was performed in ethanol at room temperature, resulting in clean conversion to the elimination product 5 in 60% yield (Scheme 3). Presumably, the reaction proceeds via 1,4-conjugate addition and not cycloaddition, with subsequent elimination of pyridine.^21,22

Scheme 3 Reagents and conditions: a, Et₃N (2 equiv.), ethanol, rt, 60%; b, Et₃N (2 equiv.), CH₂Cl₂, rt.

Significantly, crude cycloadduct 4 obtained from cycloaddition in dichloromethane at room temperature did not undergo elimination when stirred in ethanol with triethylamine. This result, when considered alongside the observation for cycloadduct 3g′ above, suggests that the reversible mechanism is not occurring in these cases. Overall, these studies underline that, for these reagents, cycloaddition and 1,4-conjugate addition reaction outcomes are under the subtle influence of solvent.

Conclusions

In summary, 1,3-dipolar cycloadditions between pyridinium ylides and 3-alkenyloxindoles that give spiroindolizidine oxindole products in high yield and with excellent regioselectivity and diastereoselectivity are reported for the first time. These cycloadducts are highly reminiscent of biologically active alkaloids, especially isorhynchophylline and strychnofoline. Specific modification of this general cycloaddition route to facilitate highly convergent access to such alkaloids and related targets is underway.

Experimental

General information

Experimental describing precursor preparation is included within the ESI.†

General procedure for preparation of cycloadducts (3). Base (2 equiv.) was added to pyridinium salt (2 equiv.) in dry solvent, under argon and the mixture stirred at room temperature for 5 minutes. Oxindole (1 equiv.) was added and the mixture stirred at room temperature for 2–4 hours. Water was added and the organic layer separated, washed with water (2×), brine, dried over Na₂SO₄, filtered and evaporated. The crude products were purified by column chromatography on silica gel (using either MeOH–CH₂Cl₂; 1/10 or EtOAc–petrol; 1/1 as eluent) or recrystallised with ethanol.

(1′R*,2′S*,3′S*,8a′S*)-Diethyl 8′-bromo-2-oxo-3′,8a′-dihydro-2′H-spiro[indoline-3,1′-indolizine]-2′,3′-dicarboxylate (3a). Brown solid; 121 mg (88%); m.p. 76–78 °C; IR (ν_max/cm⁻¹, CHCl₃) 3442, 3136, 2984, 2482, 1734, 1639, 1622, 1563, 1471, 1372, 1340, 1249, 1191; NMR δ_H (400 MHz, d⁶-DMSO) 10.68 (1H, br s, NH), 7.26–7.22 (1H, m, ArH), 7.17 (1H, d, J = 7.4 Hz, ArH), 6.91 (1H, m, ArH), 6.86 (1H, d, J = 7.4 Hz, ArH), 6.61 (1H, d, J = 7.0 Hz, N–CH=CH), 6.10 (1H, d, J = 7.0 Hz, CH–CH=CBr), 5.06 (1H, d, J = 7.0 Hz, NCH(CO₂Et), 5.00 (1H, s, NCHC–Br), 4.45 (1H, app t, J = 7.0 Hz, NCH=CH), 4.21 (2H, q, J = 7.1 Hz, NCHCO₂CH₂CH₃), 3.65 (2H, q, J = 7.1 Hz, CCH(CO₂CH₂CH₃)), 3.45 (1H, d, J = 7.0 Hz, CCH(CO₂Et), 1.23 (3H, t, J = 7.1 Hz, NCHCOCH₂CH₃), 0.62 (3H, t, J = 7.1 Hz, CCO₂CH₂CH₃); NMR δ_C (100 MHz, d⁶-DMSO) 176.2 (C), 171.4 (C), 168.4 (C), 144.0 (C), 134.9 (CH), 129.5 (CH), 128.9 (CH), 126.5 (C), 124.7 (CH), 121.5 (CH), 109.9 (CH), 106.9 (C), 93.2 (CH), 72.6 (CH), 64.8 (CH), 64.2 (C), 62.0 (CH₂), 61.4 (CH₂), 52.8 (CH), 14.5 (CH₃), 13.5 (CH₃); m/z (HRMS-ESI+) 461.0697 (M + H C₂₁H₂₂⁷⁹BrN₂O₅ requires 461.0712), 463.0700 (M + H C₂₁H₂₂⁸¹BrN₂O₅ requires 463.0692).

(1′R*,2′S*,3′S*,8a′S*)-Diethyl 5,8′-dibromo-2-oxo-3′,8a′-dihydro-2′H-spiro[indoline-3,1′-indolizine]-2′,3′-dicarboxylate (3b). Brown solid; 85 mg (93%); m.p. 68–70 °C; IR (ν_max/cm⁻¹, CHCl₃) 3437, 2982, 1732, 1639, 1618, 1564, 1465, 1373, 1309, 1130; NMR δ_H (400 MHz, d⁶-acetone) 9.84 (1H, br s, NH), 7.45–7.41 (2H, m, ArH), 6.95 (1H, dd, J = 8.2, 0.4 Hz, ArH), 6.61 (1H, d, J = 7.1 Hz, N–CH=CH), 6.14 (1H, app dt, J = 6.4, 1.0 Hz, CH–CH=CBr), 5.20 (1H, d, J = 1.0 Hz, NCHCBr), 5.05 (1H, d, J = 6.6 Hz, NCH(CO₂Et), 4.58 (1H, dd, J = 7.1, 6.4 Hz, NCH=CH), 4.27 (2H, q, J = 7.1 Hz, NCHCO₂CH₂CH₃), 3.76 (2H, q, J = 7.1 Hz, CCHCO₂CH₂CH₃), 3.69 (1H, d, J = 6.6 Hz, CCHCO₂Et), 1.29 (3H, t, J = 7.1 Hz, NCHCOCH₂CH₃), 0.78 (3H, t, J = 7.1 Hz, CCHCO₂CH₂CH₃); NMR δ_C (100 MHz, d⁶-acetone) 175.3 (C), 170.6 (C), 168.0 (C), 143.0 (C), 134.0 (CH), 131.9 (CH), 129.0 (C), 128.8 (CH), 127.5 (CH), 113.3 (C), 111.3 (CH), 106.8 (C), 93.3 (CH), 72.8 (CH), 64.8 (CH), 64.4 (C), 61.6 (CH₂), 61.1 (CH₂), 52.8 (CH), 13.6 (CH₃), 12.9 (CH₃); m/z (HRMS-ESI+) 538.9808 (M + H C₂₁H₂₁⁷⁹Br₂N₂O₅ requires 538.9812), 540.9806 (M + H C₂₁H₂₁⁸¹Br₂N₂O₅ requires 540.9792).

(1′R*,2′S*,3′S*,8a′S*)-Diethyl 8′-bromo-5-nitro-2-oxo-3′,8a′-dihydro-2′H-spiro[indoline-3,1′-indolizine]-2′,3′-dicarboxylate (3c). Yellow solid; 88 mg (91%); m.p. 83–85 °C; IR (ν_max/cm⁻¹, CHCl₃) 3249, 2981, 1745, 1626, 1603, 1455, 1343, 1125; NMR δ_H (400 MHz, d⁶-acetone) 10.30 (1H, br s, NH), 8.28 (1H, dd, J = 8.7, 2.3 Hz, ArH), 8.17 (1H, d, J = 2.3 Hz, ArH), 7.22 (1H, d, J = 8.7 Hz, ArH), 6.70 (1H, d, J = 7.1 Hz, N–CH=CH), 6.15 (1H, d, J = 6.4 Hz, CH–CH=CBr), 5.27 (1H, s, NCHC–Br), 5.15 (1H, d, J = 6.5 Hz, NCH(CO₂Et)), 4.62 (1H, dd, J = 7.1, 6.4 Hz, NCH=CH), 4.28 (2H, q, J = 7.1 Hz, NCHCO₂CH₂CH₃), 3.77 (1H, d, J = 6.5 Hz, CCH(CO₂Et)), 3.76 (2H, q, J = 7.1 Hz, CCH(CO₂CH₂CH₃)), 1.30 (3H, t, J = 7.1 Hz, NCHCOCH₂CH₃), 0.77 (3H, t, J = 7.1 Hz, CCH(CO₂CH₂CH₃)); NMR δ_C (100 MHz, d⁶-acetone) 176.0 (C), 170.4 (C), 167.9 (C), 149.9 (C), 142.4 (C), 134.0 (CH), 129.1 (CH), 127.5 (C), 126.3 (CH), 120.2 (CH), 109.7 (CH), 106.4 (C), 93.6 (CH), 73.2 (CH), 65.0 (CH), 64.2 (C), 61.7 (CH₂), 61.4 (CH₂), 52.8 (CH), 13.6 (CH₃), 12.9 (CH₃); m/z (HRMS-ESI+) 506.0569 (M + H C₂₁H₂₁⁷⁹BrN₃O₇ requires 506.0558), 508.0552 (M + H C₂₁H₂₁⁸¹BrN₃O₇ requires 508.0537).

(1′R*,2′S*,3′S*,8a′S*)-Diethyl 8′-bromo-5-methoxy-2-oxo-1-(prop-2-yn-1-yl)-3′,8a′-dihydro-2′H-spiro[indoline-3,1′-indolizine]-2′,3′-dicarboxylate (3d). Grey solid; 74 mg (82%); m.p. 125–127 °C (ethanol); IR (ν_max/cm⁻¹, CHCl₃) 3309, 3011, 1738, 1718, 1639, 1605, 1495, 1370, 1339, 1192; NMR δ_H (400 MHz, d⁶-acetone) 7.07 (1H, d, J = 8.5 Hz, ArH), 6.99 (1H, d, J = 2.4 Hz, ArH), 6.94 (1H, dd, J = 8.5, 2.4 Hz, ArH), 6.61 (1H, d, J = 7.1 Hz, N–CH=CH), 6.08 (1H, dt, J = 6.4, 0.9 Hz, CH–CH=CBr), 5.21 (1H, d, J = 0.9 Hz, NCHC–Br), 5.06 (1H, d, J = 6.9 Hz, NCH(CO₂Et)), 4.63 (1H, d, J = 17.8, 2.6 Hz, NCH_aH_b), 4.57 (1H, dd, J = 7.1, 6.4 Hz, NCH=CH), 4.50 (1H, d, J = 17.8, 2.5 Hz, NCH_aH_b), 4.27 (2H, q, J = 7.1 Hz, NCHCO₂CH₂CH₃), 3.74 (3H, s, OCH₃), 3.73 (1H, d, J = 6.9 Hz, CCH(CO₂Et), 3.72 (2H, q, J = 7.1 Hz, CCH(CO₂CH₂CH₃)), 2.80 (1H, dd, J = 2.6, 2.5 Hz, C≡CH), 1.30 (3H, t, J = 7.1 Hz, NCHCOCH₂CH₃), 0.73 (3H, t, J = 7.1 Hz, CCH(CO₂CH₂CH₃)); NMR δ_C (100 MHz, d⁶-acetone) 172.8 (C), 170.7 (C), 167.9 (C), 155.6 (C), 137.0 (C), 133.9 (CH), 128.5 (CH), 126.9 (C), 113.3 (CH), 111.8 (CH), 109.3 (CH), 106.4 (C), 93.3 (CH), 76.9 (C), 72.8 (CH), 72.7 (C), 64.8 (CH), 61.5 (CH₂), 61.0 (CH₂), 52.3 (CH), 55.1 (CH), 52.3 (CH₃), 29.2 (CH₂), 13.6 (CH₃), 12.9 (CH₃); m/z (HRMS-ESI+) 529.0957 (M + H C₂₅H₂₆⁷⁹BrN₂O₆ requires 529.0969), 531.0951 (M + H C₂₅H₂₆⁸¹BrN₂O₆ requires 531.0949).

(1′R*,2′S*,3′S*,8a′S*)-Diethyl 1-acetyl-8′-bromo-2-oxo-3′,8a′-dihydro-2′H-spiro[indoline-3,1′-indolizine]-2′,3′-dicarboxylate (3e). Yellow solid; 80 mg (83%); m.p. 108–110 °C; IR (ν_max/cm⁻¹, CHCl₃) 2981, 1744, 1710, 1636, 1561, 1466, 1370, 1308, 1272, 1191, 1023; NMR δ_H (400 MHz, d⁶-acetone) 8.22 (1H, d, J = 8.2 Hz, ArH), 7.45–7.39 (2H, m, ArH), 7.21 (1H, td, J = 8.2, 1.4 Hz, ArH), 6.63 (1H, d, J = 7.1 Hz, N–CH=CH), 6.11 (1H, d, J = 6.5 Hz, CH–CH=CBr), 5.37 (1H, s, NCHC–Br), 5.05 (1H, d, J = 7.3 Hz, NCH(CO₂Et)), 4.58 (1H, dd, J = 7.1, 6.5 Hz, NCH=CH), 4.29 (2H, q, J = 7.1 Hz, NCHCO₂CH₂CH₃), 3.86 (1H, d, J = 7.3 Hz, CCH(CO₂Et), 3.69 (2H, q, J = 7.1 Hz, CCH(CO₂CH₂CH₃)), 2.66 (3H, s, NCOCH₃), 1.31 (3H, t, J = 7.1 Hz, NCHCOCH₂CH₃), 0.69 (3H, t, J = 7.1 Hz, CCH(CO₂CH₂CH₃)); NMR δ_C (100 MHz, d⁶-acetone) 175.3 (C), 170.4 (C), 170.3 (C), 167.4 (C), 141.5 (C), 133.8 (CH), 129.4 (CH). 129.1 (CH), 125.4 (C), 124.7 (CH), 123.9 (CH), 115.9 (CH), 106.3 (C), 93.5 (CH), 74.3 (CH), 64.5 (CH), 63.8 (C), 61.7 (CH₂), 61.2 (CH₂), 53.6 (CH), 25.8 (CH₃), 13.5 (CH₃), 12.7 (CH₃); m/z (HRMS-ESI+) 503.0800 (M + H C₂₃H₂₄⁷⁹BrN₂O₆ requires 503.0813), 505.0788 (M + H C₂₃H₂₄⁸¹BrN₂O₆ requires 505.0792).

(1′S*,3′R*,8a′S*)-Ethyl 8′-bromo-2-oxo-3′,8a′-dihydro-2′H-spiro[indoline-3,1′-indolizine]-3′-carboxylate (3f). Brown solid; 107 mg (81%); m.p. 144–146 °C; IR (ν_max/cm⁻¹, CHCl₃) 3434, 2962, 2361, 1732, 1621, 1472, 1374, 1261, 1106; NMR δ_H (400 MHz, CDCl₃) 8.55 (1H, s, NH), 7.33–7.28 (2H, m, ArH), 7.09–7.04 (1H, m, ArH), 6.97 (1H, d, J = 7.3 Hz, ArH), 6.25 (1H, d, J = 7.2 Hz, NCH=CH), 6.07 (1H, d, J = 7.2 Hz, CH=CBr), 5.38 (1H, s, CH), 4.62 (1H, app.t, J = 7.2 Hz, NCH=CH), 4.44 (1H, dd, J = 8.4, 7.9 Hz, CHCO₂Et), 4.29 (2H, q, J = 7.1 Hz, CH₂CH₃), 2.52 (1H, dd, J = 13.4, 7.9 Hz, CH_aH_b), 2.22 (1H, dd, J = 13.4, 8.4 Hz, CH_aH_b), 1.35 (3H, t, J = 7.1 Hz, CH₂CH₃); NMR δ_C (100 MHz, CDCl₃) 178.0 (C), 171.7 (C), 141.1 (C), 132.8 (CH), 130.6 (C), 128.6 (CH), 127.4 (CH), 123.6 (CH), 122.5 (CH), 110.0 (CH), 109.3 (C), 94.9 (CH), 71.5 (CH), 64.1 (CH), 61.8 (CH₂), 60.9 (C), 37.7 (CH₂), 14.2 (CH₃); m/z (HRMS-ESI+) 389.0494 (M + H C₁₈H₁₈⁷⁹BrN₂O₃ requires 389.0501), 391.0476 (M + H C₁₈H₁₈⁸¹BrN₂O₃ requires 391.0480).

(1′S*,3′R*,8a′S*)-Ethyl 6′-cyano-2-oxo-3′,8a′-dihydro-2′H-spiro[indoline-3,1′-indolizine]-3′-carboxylate (3g) and (1′R*,3′R*,8a′S*)-ethyl 6′-cyano-2-oxo-3′,8a′-dihydro-2′H-spiro[indoline-3,1′-indolizine]-3′-carboxylate (3g′). Yellow solid; 90 mg (77%); m.p. 188–190 °C; IR (ν_max/cm⁻¹, CHCl₃) 3203. 2981, 2938, 2203, 1731, 1643, 1621, 1574, 1485, 1469, 1391, 1133; NMR δ_H (400 MHz, d⁶-acetone, 2 : 1 mixture of diastereoisomers, *indicates minor where different from major) 9.65 (1H, br s, NH), 9.50 (1H, br s, NH*), 7.35–7.20 (3H, m, ArH, NCC=CH), 7.07–6.95 (2H, m, ArH), 5.80 (1H, app dt, J = 10.0, 1.5 Hz, CNC–CH*=CH), 5.67 (1H, app dt, J = 10.1, 1.5 Hz, CNC–CH=CH), 5.06 (1H, t, J = 2.1 Hz, NCH*), 4.98–4.93 (2H, m, CHCO₂Et, NCH), 4.86 (1H, app t, J = 7.7 Hz, CH*CO₂Et), 4.60 (1H, ddd, J = 10.0, 2.1, 1.0 Hz, CH=CH*–CH), 4.52 (1H, ddd, J = 10.1, 2.1, 0.8 Hz, CH=CH–CH), 4.35–4.24 (2H, m, CH₂CH₃), 2.57 (1H, dd, J = 13.4, 8.6 Hz, CH_a*), 2.48–2.43 (2H, m, CH₂CHCO₂Et), 2.37 (1H, dd, J = 13.4, 7.7 Hz, CH_b*), 1.30 (3H, t, J = 7.1 Hz, CH₂CH₃); NMR δ_C (100 MHz, d⁶-acetone) 179.3 (C), 176.5 (C), 171.8 (C), 171.6 (C), 147.8 (CH), 146.6 (CH), 143.5 (C), 142.3 (C), 132.1 (C), 129.8 (CH), 129.4 (CH), 127.9 (C), 126.4 (C), 124.7 (CH), 124.0 (CH), 123.7 (CH), 123.2 (CH), 123.0 (CH), 120.9 (C), 120.7 (C) 111.9 (CH), 111.5 (CH), 110.7 (CH), 110.2 (CH), 78.6 (C), 78.4 (C), 67.8 (CH), 67.4 (CH), 63.9 (CH), 63.2 (CH), 62.4 (CH₂), 62.3 (CH₂), 37.2 (CH₂), 34.9 (CH₂), 14.5 (CH₃); m/z (HRMS-ESI+) 358.1162 (M + Na C₁₉H₁₇N₃NaO₃ requires 358.1162).

(1′R*,3′S*,8a′R*)-Ethyl 6′-carbamoyl-2-oxo-3′,8a′-dihydro-2′H-spiro[indoline-3,1′-indolizine]-3′-carboxylate (3h) and (1′R*,3′S*,8a′S*)-ethyl 6′-carbamoyl-2-oxo-3′,8a′-dihydro-2′H-spiro[indoline-3,1′-indolizine]-3′-carboxylate (3h′). Yellow solid; 109 mg (95%); m.p. 138–140 °C; IR (ν_max/cm⁻¹, CHCl₃) 3352. 2926, 2359, 2340, 1710, 1648, 1620, 1585, 1471, 1382, 1290, 1196, 1104; NMR δ_H (400 MHz, d⁶-DMSO, 7 : 3 mixture of diastereoisomers, *indicates minor where different from major) 10.63 (1H, s, NH), 10.40 (1H, s, NH*), 7.38 (2H, s, CH=CCONH₂), 7.27–7.16 (4H, m, ArH), 7.02–6.84 (4H, m, ArH), 6.54 (4H, br s, NH₂), 6.28 (1H, dt, J = 10.2, 2.1 Hz, NH₂COC–CH*=CH), 6.14 (1H, dt, J = 10.2, 2.1 Hz, NH₂COC–CH=CH), 4.95 (1H, dd, J = 8.8, 7.4 Hz, CHCO₂Et), 4.92 (1H, dd, J = 8.8, 7.4 Hz, CH*CO₂Et), 4.78 (2H, app dd, J = 2.1, 0.6 Hz, NCH), 4.38 (1H, ddd, J = 10.2, 2.1, 0.6 Hz, CH=CH*–CH), 4.35 (1H, ddd, J = 10.2, 2.1, 0.6 Hz, CH=CH–CH), 4.24 (4H, m, CH₂CH₃), 2.47 (1H, dd, J = 13.3, 8.8 Hz, CH_a*H_b), 2.35–2.17 (2H, m, CH_b*, CH_aH_b), 1.29 (3H, t, J = 7.1 Hz, CH₂CH₃*), 1.27 (3H, t, J = 7.1 Hz, CH₂CH₃); NMR δ_C (100 MHz, d⁶-DMSO) 179.3 (C), 176.6 (C), 172.2 (C), 172.1 (C), 167.4 (C), 167.3 (C), 143.0 (C), 142.6 (CH), 141.9 (C), 141.5 (CH), 132.0 (C) 129.0 (CH), 128.7 (CH), 128.0 (C) 124.8 (CH), 124.2 (CH), 124.1 (CH), 123.2 (CH), 122.1 (CH), 122.0 (CH) 110.0 (CH), 109.9 (CH), 109.1 (CH), 107.5 (CH), 101.1 (C), 101.0 (C), 68.1 (CH), 67.5 (CH), 63.5 (CH), 62.6 (CH), 61.8 (CH₂), 61.7 (CH₂), 55.6 (C), 55.4 (C), 36.5 (CH₂), 34.3 (CH₂), 14.6 (CH₃), 14.5 (CH₃); m/z (HRMS-ESI+) 354.1442 (M + H C₁₉H₂₀N₃O₄ requires 354.1454).

(1′R*,3′S*,8a′R*)-Ethyl 6′-acetyl-2-oxo-3′,8a′-dihydro-2′H-spiro[indoline-3,1′-indolizine]-3′-carboxylate (3i) and (1′R*,3′S*,8a′S*)-ethyl 6′-acetyl-2-oxo-3′,8a′-dihydro-2′H-spiro[indoline-3,1′-indolizine]-3′-carboxylate (3i′). Brown solid, 97 mg (81%); m.p. 118–120 °C; IR (ν_max/cm⁻¹, CHCl₃) 3434, 3010, 2447, 1731, 1621, 1573, 1472, 1373, 1251, 1180; NMR δ_H (400 MHz, CDCl₃, 1 : 1.3 mixture of diastereoisomers, *indicates minor where different from major) 8.35 (1H, s, NH*), 8.21 (1 H, s, NH), 7.47 (1H, s, NCH*=CCOCH₃), 7.42 (1H, s, NCH=CCOCH₃), 7.27–6.94 (8H, m, ArH), 6.53 (1H, d, J = 10.3 Hz, (COCH₃)CH=CH–CH), 6.36 (1H, d, J = 10.3 Hz, (COCH₃)CH*=CH–CH), 5.18 (1H, t, J = 1.8 Hz, (COCH₃)CH=CH–CH*), 5.05 (1H, t, J = 1.8 Hz, (COCH₃)CH=CH–CH), 4.81 (1H, t, J = 7.8 Hz, CHCO₂Et), 4.67 (1H, dd, J = 10.3, 1.8 Hz, (COCH₃)CH=CH–CH) 4.61 (1H, t, J = 7.8 Hz, CH*CO₂Et) 4.53 (1H, dd, J = 10.3, 1.8 Hz, (COCH₃)CH=CH*–CH), 4.38–4.30 (4H, m, CH₂CH₃), 2.70–2.58 (2H, m, CH–CH_aCH_b), 2.45–2.33 (2H, m, CH–CH_aCH_b), 2.18 (3H, s, COCH₃*), 2.13 (3H, s, COCH₃), 1.41–1.34 (3H, m, CH₂CH₃); NMR δ_C (100 MHz, CDCl₃) 191.8 (C), 179.6 (C), 176.8 (C), 171.2 (C), 170.6 (C), 146.2 (CH), 144.3 (CH), 141.6 (C), 140.3 (C), 130.7 (C), 129.2 (CH), 128.9 (CH), 126.8 (C), 123.9 (CH), 123.7 (CH), 123.5 (CH), 123.2 (CH), 122.9 (CH), 122.8 (CH), 122.6 (CH), 110.4 (CH), 110.3 (CH), 108.7 (CH), 68.1 (CH), 67.1 (CH), 63.3 (CH), 62.8 (CH), 62.4 (CH₂), 62.2 (CH₂), 58.8 (C), 58.4 (C), 36.9 (CH₂), 34.4 (CH₂), 14.2 (CH₃); m/z (HRMS-ESI+) 353.1498 (M + H C₂₀H₂₁N₂O₄ requires 353.1501).

(1′R*,3′S*,8a′S*)-3′-Acetyl-8′-bromo-3′,8a′-dihydro-2′H-spiro[indoline-3,1′-indolizin]-2-one (3j). Brown solid; 63 mg (76%); m.p. 126–128 °C; IR (ν_max/cm⁻¹, CHCl₃) 3438, 3011, 2928, 2437, 1780, 1721, 1622, 1471, 1426, 1390, 1240, 1170; NMR δ_H (400 MHz, d⁶-DMSO) 10.53 (1H, s, NH), 7.27–7.19 (2H, m, 2× ArH), 6.96 (1H, td, J = 7.6, 1.0 Hz, ArH), 6.86 (1H, d, J = 7.6 Hz, ArH), 6.43 (1H, d, J = 7.0 Hz, CH–CH=CBr), 6.09 (1H, d, J = 7.0 Hz, N–CH=CH), 4.88 (1H, s, NCH), 4.70 (1H, t, J = 7.0 Hz, NCH=CH), 4.49 (1H, t, J = 6.8 Hz, CHCOCH₃), 2.19 (3H, s, COCH₃), 2.11–2.06 (2H, m, CH_aH_b); NMR δ_C (100 MHz, d⁶-DMSO) 207.3 (C), 177.7 (C), 142.8 (C), 135.2 (CH), 131.3 (C), 128.7 (CH), 128.2 (CH), 123.8 (CH), 121.8 (CH), 109.9 (CH), 108.0 (C), 93.3 (CH), 71.7 (CH), 70.5 (CH), 61.3 (C), 36.4 (CH₂), 26.7 (CH₃); m/z (HRMS-ESI+) 359.0370 (M + H C₁₇H₁₆⁷⁹BrN₂O₂ requires 359.0395), 361.0359 (M + H C₁₇H₁₆⁸¹BrN₂O₂ requires 361.0375).

(2′S*,3′S*,8a′S*)-Diethyl 8′-fluoro-2-oxo-3′,8a′-dihydro-2′H-spiro[indoline-3,1′-indolizine]-2′,3′-dicarboxylate (3k). Yellow oil; 80 mg (87%); IR (ν_max/cm⁻¹, CHCl₃) 3691, 3440, 3010, 1736, 1620, 1597, 1472, 1391, 1314, 1192, 1025; NMR δ_H (400 MHz, d⁶-acetone) 9.66 (1H, br s, NH), 7.26–7.22 (2H, m, ArH), 6.97–6.91 (2H, m, ArH), 6.35–6.32 (1H, m, N–CH=CH), 5.39–5.34 (1H, m, CH–CH=CF), 5.17 (1H, s, NCHC–F), 5.03 (1H, dd, J = 7.4, 1.2 Hz, NCH(CO₂Et)), 4.54–4.49 (1H, m, NCH=CH), 4.27 (2H, q, J = 7.1 Hz, NCHCO₂CH₂CH₃), 3.81–3.66 (3H, m, NCH(CO₂Et)CH(CO₂Et), NCH(CO₂Et)CH(CO₂CH₂CH₃)), 1.29 (3H, t, J = 7.1 Hz, NCHCOCH₂CH₃), 0.70 (3H, t, J = 7.1 Hz, NCH(CO₂Et)CH(CO₂CH₂CH₃)); NMR δ_C (100 MHz, d⁶-acetone) 174.9 (C), 170.9 (C), 168.1 (C), 149.3 (d, J^C–F = 252 Hz, C), 143.0 (C), 130.5 (d, J^C–F = 4 Hz, CH), 129.0 (CH), 126.6 (C), 124.6 (CH), 121.3 (CH), 109.6 (CH), 103.1 (d, J^C–F = 14 Hz, CH), 91.1 (d, J^C–F = 5 Hz, CH), 68.0 (d, J^C–F = 33 Hz, CH), 65.3 (d, J^C–F = 1 Hz, CH), 62.6 (d, J^C–F = 3 Hz, C), 61.5 (CH₂), 60.9 (CH₂), 52.9 (CH), 13.6 (CH₃), 12.8 (CH₃); m/z (HRMS-ESI+) 401.1507 (M + H C₂₁H₂₂FN₂O₅ requires 401.1507).

(1′R*,2′S*,3′S*,8a′R*)-Diethyl 2-oxo-3′,5′,6′,7′,8′,8a′- hexahydro-2′H-spiro[indoline-3,1′-indolizine]-2′,3′-dicarboxylate (3l). Following the general procedure described above but the product was not stable to chromatography on silica gel, so the crude cycloadduct 4 was reduced without purification using the following procedure.

Crude cycloadduct 4 (75 mg) and RANEY® nickel (10 mol%) were dissolved in anhydrous ethyl acetate (4 mL), under argon. The atmosphere was replaced with H₂ and the mixture stirred until reduction was complete by TLC analysis and then filtered through a pad of Celite. The filtrate was concentrated in vacuo and purified via column chromatography (EtOAc–petrol; 1/4) to give spiroindolizidine 3l as a yellow oil; 48 mg (63%); IR (ν_max/cm⁻¹, CHCl₃) 3440, 3198, 2942, 1732, 1621, 1471, 1373, 1339, 1319, 1184, 1097; NMR δ_H (400 MHz, CDCl₃) 8.66 (1H, br s, NH), 7.31 (1H, d, J = 7.6 Hz, ArH), 7.22 (1H, td, J = 7.6, 1.0 Hz, ArH), 7.00 (1H, t, J = 7.6 Hz, ArH), 6.92 (1H, d, J = 7.6 Hz, ArH), 4.59 (1H, d, J = 5.6 Hz, NCHCO₂Et), 4.35–4.20 (2H, m, NCH(COCH₂CH₃)), 4.00 (1H, d, J = 5.6 Hz, NCH(CO₂Et)CH), 3.81–3.61 (2H, m, CH(COCH₂CH₃)), 3.41 (1H, dd, J = 10.9, 2.4 Hz, NCHC)), 3.09 (1H, d, J = 9.5 Hz, CH_aH_b), 2.45 (1H, t, J = 9.5 Hz, CH_aH_b), 1.64–1.53 (2H, m, CH_aH_b, CH_aH_b), 1.42–1.12 (6H, m, CH_aH_b, CH_aH_b, CH_aCH_b, CH₂CH₃), 0.74–0.64 (4H, m, CH₂CH₃, CH_aCH_b); NMR δ_C (100 MHz, CDCl₃) 178.4 (C), 172.4 (C), 143.1 (C), 131.7 (C), 128.2 (CH), 126.5 (C), 125.8 (CH), 122.2 (CH), 109.4 (CH), 67.7 (CH), 64.1 (CH), 60.9 (CH₂), 60.6 (CH₂), 60.0 (C), 54.2 (CH), 47.5 (CH₂), 25.9 (CH₂), 25.3 (CH₂), 22.6 (CH₂), 14.4 (CH₃), 13.3 (CH₃); m/z (HRMS-ESI+) 387.1908 (M + H C₂₁H₂₇N₂O₅ requires 387.1920).

(1′S*,2′R*,3′R*,8a′R*)-Ethyl 8′-bromo-3′-cyano-2-oxo-3′,8a′-dihydro-2′H-spiro[indoline-3,1′-indolizine]-2′-carboxylate (3m). White solid; 145 mg (72%); m.p. 159–161 °C (acetone); IR (ν_max/cm⁻¹, CHCl₃) 3691, 3439, 3009, 2482, 2245, 1735, 1640, 1621, 1569, 1485, 1378, 1191; NMR δ_H (400 MHz, d⁶-acetone) 9.74 (1H, br s, NH), 7.28 (1H, app t, J = 7.6 Hz, ArH), 7.22 (1H, d, J = 7.3 Hz, ArH), 7.01–6.91 (2H, m, ArH), 6.67 (1H, d, J = 7.2, N–CH=CH), 6.12 (1H, d, J = 6.4 Hz, CH–CH=CBr), 5.48 (1H, d, J = 6.4 Hz, NCHCN, 5.25 (1H, s, NCHC–Br), 4.72 (1H, app t, J = 6.4 Hz, NCH=CH), 3.77 (1H, d, J = 6.4 Hz, CHCO₂CH₂CH₃), 3.72 (2H, q, J = 7.1 Hz, CCH(CO₂CH₂CH₃)), 0.74 (3H, t, J = 7.1 Hz, NCHCOCH₂CH₃); NMR δ_C (100 MHz, d⁶-DMSO) 176.1 (C), 167.9 (C), 144.6 (C), 132.8 (CH), 130.3 (CH), 129.1 (CH), 126.7 (C), 125.5 (CH), 122.3 (CH), 119.1 (C), 110.6 (CH), 109.1 (C), 96.7 (CH), 72.9 (CH), 63.8 (C), 62.3 (CH₂), 55.6 (CH), 54.9 (CH), 13.7 (CH₃); m/z (HRMS-ESI+) 436.0273 (M + Na C₁₉H₁₆⁷⁹BrN₃NaO₃ requires 436.0273), 438.0256 (M + Na C₁₉H₁₆⁸¹BrN₃NaO₃ requires 438.0256).

(1′S*,2′R*,3′R*,8a′R*)-Ethyl 8′-bromo-2-oxo-3′-phenyl-3′,8a′-dihydro-2′H-spiro[indoline-3,1′-indolizine]-2′-carboxylate (3n). White solid; 149 mg (70%); m.p. 176–178 °C (acetone); IR (ν_max/cm⁻¹, CHCl₃) 3692, 3441, 3009, 1731, 1601, 1562, 1484, 1379, 1247, 1117, 1027; NMR δ_H (400 MHz, d⁶-acetone) 9.71 (1H, br s, NH), 7.51–7.41 (5H, m, ArH), 7.36–7.25 (2H, m, ArH), 7.01 (1H, td, J = 7.7, 0.8 Hz, ArH), 6.97 (1H, d, J = 7.7 Hz, ArH), 6.32 (1H, d, J = 6.7 Hz, N–CH=CH), 6.07 (1H, d, J = 6.7 Hz, CH–CH=CBr), 5.43 (1H, d, J = 8.5 Hz, NCHPh, 4.51 (1H, app t, J = 6.7 Hz, CH=CHN), 3.78 (1H, dq, J = 10.8, 7.1 Hz, CH_aH_b), 3.67 (1H, dq, J = 10.8, 7.1 Hz, CH_aH_b), 3.4 (1H, d, J = 8.5 Hz, CHCO₂Et), 0.77 (3H, t, J = 7.1 Hz, CH₃); NMR δ_C (100 MHz, d⁶-acetone) 176.6 (C), 169.3 (C), 144.5 (C), 143.2 (C), 134.6 (CH), 130.0 (CH), 129.9 (CH), 129.4 (CH), 128.7 (CH), 127.5 (C), 127.2 (CH), 125.6 (CH), 122.2 (CH), 110.4 (CH), 108.3 (C), 94.1 (CH), 73.7 (CH), 68.1 (CH), 64.8 (C), 61.6 (CH₂), 59.4 (CH), 13.8 (CH₃); m/z (HRMS-ESI+) 465.0800 (M + H C₂₄H₂₂⁷⁹BrN₂O₃ requires 465.0808), 467.0786 (M + H C₂₄H₂₂⁸¹BrN₂O₃ requires 465.0793).

Diethyl 2-(2-oxoindolin-3-ylidene)succinate 5. Method as cycloaddition, but ethanol was used as solvent and reaction performed at 50 °C. Yellow oil (60%); NMR δ_H (400 MHz, CDCl₃, 5 : 1 mixture of diastereoisomers, only major diastereoisomer peaks are quoted) (ν_max/cm⁻¹, CHCl₃) 3446, 3011, 2986, 1726, 1617, 1470, 1370, 1334, 1295, 1192; NMR δ_H (400 MHz, CDCl₃) 8.38 (1H, s, NH), 7.66 (1H, d, J = 8.0 Hz, ArH), 7.29 (1H, td, J = 8.0, 1.2 Hz, ArH), 6.98 (1H, td, J = 8.0, 1.2 Hz, ArH), 6.85 (1H, d, J = 8.0 Hz, ArH), 4.43 (2H, q, J = 7.2 Hz, CH₂CH₃), 4.41 (2H, s, CH₂CO₂Et), 4.22 (2H, q, J = 7.2 Hz, CH₂CH₃), 1.40 (3H, t, J = 7.2 Hz, CH₂CH₃), 1.29 (3H, t, J = 7.2 Hz, CH₂CH₃); NMR δ_C (100 MHz, CDCl₃) 169.7 (C), 169.2 (C), 167.4 (C), 141.0 (C), 135.0 (C), 130.9 (CH), 129.4 (C), 125.1 (CH), 122.3 (CH), 120.8 (C), 109.9 (CH), 61.9 (CH₂), 61.2 (CH₂), 34.7 (CH₂), 14.2 (CH₃), 14.0 (CH₃); m/z (HRMS-ESI+) 326.0982 ([M + Na] 100%) requires C₁₆H₁₇NO₅Na⁺ 326.0999.

Acknowledgements

This work was supported by the EPSRC (MU, EP/J021008/1), AstraZeneca (JD) and the University of Nottingham (RAC).

Notes and references

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17. For a related synthetic process: B. Viswambharan, K. Selvakumar, S. Madhavan and P. Shanmugam, Org. Lett., 2010, 12, 2108–2111.
18. G. Laus, J. Chem. Soc., Perkin Trans. 2, 1998, 315–317.
19. Diastereoisomers, such as 3g : 3g′ could not be separated by column chromatography on silica gel. No change was observed to the diastereomeric ratio in the crude product obtained from cycloaddition reactions performed in various solvents at a range of temperatures.
20. Q. Fu and C.-G. Yan, Tetrahedron, 2013, 69, 5841–5849.
21. For related solvent effects: N. E. Dontsova, V. N. Nesterov and A. M. Shestopalov, Tetrahedron, 2013, 69, 5016–5021.
22. A very recent paper describing stepwise reaction of pyridinium ylides with Michael acceptors: D. S. Allgäuer and H. Mayr, Eur. J. Org. Chem., 2013 DOI:10.1002/ejoc.201300784.

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Footnotes

† Electronic supplementary information (ESI) available: Full experimental and spectroscopic information. CCDC 927102–927103. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c3ob41415a

‡ Crystal data for 3a. C₂₁H₂₁BrN₂O₅, M = 507.38, triclinic, a = 8.5537(12), b = 9.0560(14), c = 16.2097(17) Å, U = 1147.4(3) ų. T = 120(2)K, space group P1̄, Z = 2, 8522 reflections measured, 4490 unique with R = 0.0804, wR₂ = 0.2241. CCDC 927103. Crystal data for 3g′. C₁₉H₁₇N₃O₃, M = 335.35, triclinic, a = 8.8865(5), b = 9.3125(3), c = 10.9460(5) Å, U = 826.26(7) ų. T = 120(2) K, space group P1̄, Z = 2, 15 441 reflections measured, 3480 unique with R = 0.0346, wR₂ = 0.0903. CCDC 927102.

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